Fibrinogen Is a Marker for Nephropathy and Peripheral Vascular Disease in Type 1 Diabetes

Abstract

-We examined whether plasma fibrinogen levels and the ␤-fibrinogen gene G Ϫ455 3 A polymorphism were related to microvascular or macrovascular disease in patients (n ϭ 909) with type 1 diabetes enrolled in the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC). Univariate regression showed that fibrinogen levels were correlated with BMI (r ϭ 0.15; P Ͻ 0.0001), HbA 1c (r ϭ 0.11; P ϭ 0.0014), total cholesterol (r ϭ 0.17; P Ͻ 0.0001), and LDL cholesterol (r ϭ 0.16; P Ͻ 0.0001) in all patients. In men, but not women, waist-to-hip ratio (r ϭ 0.20; P Ͻ 0.0001) and triglycerides (r ϭ 0.13; P ϭ 0.0047) also became powerful predictors of fibrinogen level; in women, but not men, fibrinogen was correlated with both diastolic (r ϭ 0.16; P ϭ 0.0011) and systolic (r ϭ 0.11; P ϭ 0.0241) blood pressure. Fibrinogen was correlated with urinary albumin excretion rates in men (r ϭ 0.13; P ϭ 0.0033), but not in women. In both sexes, however, the development of proteinuria (albumin excretion Ͼ300 mg/24 h) was accompanied by 1.5-fold increment in plasma fibrinogen compared with patients with normal excretion or microalbuminuria. In addition, high fibrinogen levels were associated with a lower average ankle-brachial index in women (r ϭ Ϫ0.13; P ϭ 0.0075), but not men. Multiple regression analyses demonstrated that plasma fibrinogen was independently correlated with high albumin excretion rate in men, and with low average ankle-brachial index in women. Fibrinogen was not correlated with the severity of retinopathy. Carotid artery intima-medial thickness was not correlated with fibrinogen, and the G Ϫ455 3 A polymorphism in the 5Ј promoter region of the ␤-fibrinogen gene did not influence circulating fibrinogen levels. However, the presence of the more common G Ϫ455 allele was associated with greater intima-medial thickness in the internal carotid artery (ANCOVA P ϭ 0.045). Last, hyperfibrinogenemia in type 1 diabetes is associated with components of the insulin resistance syndrome trait cluster, and the association is influenced by sex.

Fibrinogen and AER are major independent predictors of 11-year cardiovascular mortality in type 2 diabetes: the Casale Monferrato Study

“…It has been suggested that the hyperglycaemia-induced formation of reactive oxygen species in mitochondria and the generation of AGE might be the link between endothelial cell damage and damage to glomerular cells, leading to albuminuria [30]. Fibrinogen has been found to predict progression of nephropathy [8][9][10], probably as a marker of renal vascular damage; however, its role in diabetic subjects could be even more complex than that of an indicator of atherothrombotic disease. Indeed, emerging evidence suggests that chronic inflammation may represent a component of the metabolic syndrome, as it has been associated with insulin resistance and cardiovascular risk factors in diabetic subjects [31,32].…”

“…Moreover, cross-sectional studies have provided evidence that fibrinogen levels are independently associated with AER in both type 1 and type 2 diabetic subjects [8][9][10]; however, the pathophysiological relationship between these two factors and the clinical relevance of their combined effect on cardiovascular risk remain unknown. Recent prospective data from the Casale Monferrato Study have provided evidence that hyperfibrin-ogenaemia independently predicts progression to overt diabetic nephropathy in type 2 diabetes [11].…”

Acute-Phase Markers of Inflammation and Glomerular Structure in Patients with Type 2 Diabetes

“…In type 2 diabetes, fibrinogen levels have been demonstrated to predict the progression to overt nephropathy (10). Hyperfibrinogenemia, an indicator of inflammation, is also associated with the presence of endothelial dysfunction, insulin resistance, hypercoagulability, and increased blood viscosity and is a marker of unstable atherosclerotic lesions (11)(12)(13)(14)(15). The aim of the present study was to explore the relationships between low-grade inflammation markers, glomerular structure, and renal function in patients with type 2 diabetes.…”

“…Also fibrinogen has been reported to be associated with both cardiovascular risk and nephropathy in type 1 and type 2 diabetes (10,11). The Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications (DCCT/EDIC) study group reported that fibrinogen is associated with AER, especially in men, but not with retinopathy and that a fibrinogen gene polymorphism is associated with peripheral vascular disease (11).…”

“…The Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications (DCCT/EDIC) study group reported that fibrinogen is associated with AER, especially in men, but not with retinopathy and that a fibrinogen gene polymorphism is associated with peripheral vascular disease (11). It is interesting that hyperfibrinogenemia was associated with components of the insulin-resistance trait cluster (11). In type 2 diabetes, fibrinogen levels have been demonstrated to predict the progression to overt nephropathy (10).…”